Methadone, 6-dimethylamino-4,4-diphenyl-3-heptanone, is a synthetic narcotic analgesic developed during World War II by the German chemists, Bockmuhl and Ehrhart, Ann., 561,52 (1948). The synthesis of methandone by their procedure begins with the reaction of diphenylacetonitrile and 1-dimethylamino-2-chloropropane in the presence of sodamide. A high yield of alkylation products is obtained comprising a mixture of two isomeric alkylated diphenylacetonitriles in approximately equal amounts. The nitriles are respectively (I) 2,2-diphenyl-4-dimethylaminovaleronitrile (mp 91.degree.-92.degree. C.) and (II) 2,2-diphenyl-3-methyl-4-dimethylaminobutyronitrile (mp 69.degree.-70.degree. C.). The high melting nitrile, upon reaction with ethyl magnesium bromide and subsequent hydrolysis, yields methadone. The low melting nitrile reacts with ethyl magnesium bromide to give a stable ketimine, 3-imino-4,4-diphenyl-5-methyl-6-dimethylaminohexane, which is hydrolyzed with difficulty to the ketone, isomethadone.
The production of these two isomeric nitriles in a single reaction is explained as follows: In the course of the reaction, 1-dimethylamino-2-chloropropane cyclizes to yield 1,1,2-trimethylaziridinium chloride of the following structure: ##STR1##
The aziridinium ring is quite unstable and reacts with the diphenylacetonitrile anion (produced under basic conditions) to yield the mixture of isomeric alkylated nitriles set forth above. When the aziridinium ring opens with a breaking of the bond marked with a small a, the desired nitrile I is produced while the rupture of the aziridinium bond marked with a small b yields the isomeric nitrile. Naturally since, on further reaction, nitrile I yields methadone and the nitrile II yields isomethadone, not a useful analgesic, it has been thought desirable to maximize the yields of the desired nitrile I by finding reaction conditions which favored the rupturing of the aziridinium ring at bond a. Many experiments, however, using different solvents, temperatures, etc. yielded, within experimental error, the same ratio of nitrile I and nitrile II, thus leading to the conclusion that the ring opening reaction was a first order reaction and thus independent of environment.
The methadone literature is too voluminous to be reviewed, but the above chemistry is set forth in one or more of the following publications: Schultz et al., J. Am. Chem. Soc., 69, 188,2454 (1947), Cheney et al., ibid, 71, 53, (1949); Easton et al., ibid, 69,2941 (1947), M. M. Baizer, Bull. on Narcotics, U.N. 5 (1), 32 (1953) (a review article). Methadone is referred to as amidon in some of the above publications.
The only reference to a procedure other than the sodamide-toluene or t-butoxide--t-butanol solvent procedures of the above references for the alkylation of diphenylacetonitrile is Cusic, J. Am. Chem. Soc., 71, 3546 (1949). Cusic employed a melt with 1-dimethylamino-2-chloropropane, diphenylacetonitrile and sodium hydroxide in the absence of a solvent. In my hands, both the Cusic and Bockmuhl procedures yield at best a 6:4 isomer ratio of the desired isomer to the undesired (isomethandone intermediate) isomer.
It is an object of this invention to provide an alkylation step in a procedure for the preparation of methadone involving the reaction of 1-dimethylamino-2-chloropropane and diphenylacetonitrile such that the ratio of the desired to undesired isomer is greater than 6:4.